Guidelines bipolar disorders

The World Journal of Biological Psychiatry, 2009; 10(2): 85Á116 GUIDELINES Downloaded By: [World Federation of Societies of Biological Psychiatry] At: 11:39 19 May 2009 The World Federation of Societies of Biological Psychiatry (WFSBP) Guidelines for the Biological Treatment of Bipolar Disorders: Update 2009 on the Treatment of Acute Mania HEINZ GRUNZE1,2, EDUARD VIETA3, GUY M GOODWIN4, CHARLES BOWDEN5, ă LLER2, SIEGFRIED KASPER7 & ă RGEN MO RASMUS W LICHT6, HANS-JU WFSBP TASK FORCE ON TREATMENT GUIDELINES FOR BIPOLAR DISORDERS8* Institute of Neuroscience, Newcastle University, Newcastle upon Tyne, UK, 2Department of Psychiatry, LudwigMaximilians-University, Munich, Germany, 3Bipolar Disorders Programme, Institute of Neuroscience, Hospital Clinic, University of Barcelona, IDIBAPS, CIBERSAM, Barcelona, Catalonia, Spain, 4Department of Psychiatry, Warneford Hospital, University of Oxford, Oxford, UK, 5Department of Psychiatry, University of Texas Health Science Center, San Antonio, TX, USA, 6Mood Disorders Research Unit, Aarhus University Hospital, Risskov, Denmark, 7Department of Psychiatry and Psychotherapy, Medical University of Vienna, Vienna, Austria, and 8WFSBP Task Force on Treatment Guidelines for Bipolar Disorders Abstract These updated guidelines are based on a first edition that was published in 2003, and have been edited and updated with the available scientific evidence until end of 2008 Their purpose is to supply a systematic overview of all scientific evidence pertaining to the treatment of acute mania in adults The data used for these guidelines have been extracted from a MEDLINE and EMBASE search, from the clinical trial database clinicaltrials.gov, from recent proceedings of key conferences, and from various national and international treatment guidelines Their scientific rigor was categorised into six levels of evidence (AÁF) As these guidelines are intended for clinical use, the scientific evidence was finally asigned different grades of recommendation to ensure practicability Key words: Bipolar disorder, mania, depression, acute treatment, evidence-based guidelines, pharmacotherapy, antipsychotics, mood stabiliser, electroconvulsive therapy Abbreviations ADHD Attention-deficit-hyperactivity disorder CBT Cognitive behavioral therapy CE Category of evidence DSM ECT HDL ICD LDL Diagnostic and Statistical Manual Electroconvulsive therapy High density lipoproteins International Clssification of Diseases Low density lipoproteins Correspondence: Prof Dr Heinz Grunze, Institute of Neuroscience, Department of Psychiatry, RVI, Newcastle University, Newcastle upon Tyne NE1 4LP, UK Tel: '44 191 282 5765 Fax: '44 191 222 6162 E-mail: Heinz.Grunze@ncl.ac.uk *Chairman: Siegfried Kasper (Austria), Co-Chairman: Guy Goodwin (United Kingdom), Co-Chairman: Charles Bowden (USA), Secretary: Heinz Grunze (United Kingdom), WFSBP Past-President: Hans-Juărgen Moăller (Germany), Eduard Vieta (Spain); Members: Hagop Akiskal (USA), Jose´Luis Ayuso-Gutierrez (Spain), Michael Bauer (Germany), Per Bech (Denmark), Michael Berk (Australia), Istvan Bitter (Hungary), Graham Burrows (Australia), Joseph Calabrese (USA), Giovanni Cassano (Italy), Marcelo Cetkovich-Bakmas (Argentina), John C Cookson (United Kingdom), I Nicol Ferrier (United Kingdom), Wagner F Gattaz (Brazil), Frederik K Goodwin (USA), Gerhard Heinze (Mexico), Teruhiko Higuchi (Japan), Robert M Hirschfeld (USA), Cyril Hoeschl (Czech Republik), Edith Holsboer-Trachsler (Switzerland), Kay Redfield Jamison (USA), Cornelius Katona (UK), Martin Keller (USA), E Kostukova (Russia), Hever Kruger (Peru), Parmanand Kulhara (India), Yves Lecruibier (France), Veronica Larach (Chile), Rasmus W Licht (Denmark), Odd Lingjaerde (Norway), Henrik Lublin (Denmark), Mario Maj (Italy), Julien Mendlewicz (Belgium), Roberto Miranda Camacho (Mexico), Philip Mitchell (Australia), S Mosolov (Russia), Stuart Montgomery (United Kingdom), Charles Nemeroff (USA), Willem Nolen (The Netherlands), Eugene S Paykel (United Kingdom), Robert M Post (USA), Stanislaw Puzynski (Poland), Zoltan Rihmer (Hungary), Janusz K Rybakowski (Poland), Per Vestergaard (Denmark), Peter C Whybrow (USA), Kazuo Yamada (Japan) ISSN 1562-2975 print/ISSN 1814-1412 online # 2009 Informa UK Ltd (Informa Healthcare, Taylor & Francis AS) DOI: 10.1080/15622970902823202 86 H Grunze et al MAS MRS Bech-Rafaelsen Mania Scale Mania Rating Scale (subset of items derived from the Schedule for Affective Disorders and Schizophrenia-Change Bipolar Scale (SADS-CB)) rTMS Repetitive transcranial magnetic stimulation RCT Randomized controlled trial RG Recommendation grade WFSBP World Federation of Societies of Biological Psychiatry YMRS Young Mania Rating Scale Downloaded By: [World Federation of Societies of Biological Psychiatry] At: 11:39 19 May 2009 Preface and Disclosure Statement As the other guidelines of this series, these practice guidelines for the biological, mainly pharmacological treatment of acute bipolar mania were developed by an international Task Force of the World Federation of Societies of Biological Psychiatry (WFSBP) The preparation of these guidelines has not been financially supported by any commercial organization This practice guideline has mainly been developed mainly by psychiatrists and psychotherapists who are in active clinical practice In addition, some contributors are primarily involved in research or other academic endeavors It is possible that through such activities some contributors have received income related to medicines discussed in this guideline A number of mechanisms are in place to minimize the potential for producing biased recommendations due to conflicts of interest Some drugs recommended in the present guideline may not be available in all countries, and approved doses may vary Introduction Bipolar disorder is frequently misdiagnosed and under-diagnosed (Kasper et al 2002; Angst 2006) although occasionally overdiagnosis may occur (Zimmerman et al 2008) Particularly when unrecognised or misdiagnosed, and consequently ineffectively treated, bipolar disorder constitutes a devastating illness (Simpson and Jamison 1999; Morselli et al 2004; Maina et al 2007) with a significant socioeconomic burden (Woods 2000; Angst 2004; van Hakkaart et al 2004; Runge and Grunze 2004) At first manifestation, the diagnosis of bipolar disorder may not be obvious; at least 20% and in some settings up to 50% of patients diagnosed with an index episode of depression may prove to be bipolar in the long run (Goldberg et al 2001; Angst 2006) However, when the disorder presents as acute mania, which is the focus of the present guidelines, the diagnosis becomes easier, albeit it sometimes can be difficult to differentiate from schizophrenia and other conditions like severe ADHD In contrast to unipolar depression and to the more broadly defined bipolar spectrum, bipolar I disorder (characterized primarily by mania) as defined by the Diagnostic and Statistical Manual, 4th ed-TR (DSM-IV (American Psychiatric Association 1994) seems to have a worldwide lifetime incidence within a relatively narrow range between 0.5 and 1.6% for bipolar I disorder (Weissman et al 1996) The reported lifetime prevalence for bipolar spectrum disorders (Bipolar I, II or NOS) is about 5.5% (Angst 1995; Regeer et al 2004), although slight deviations of these numbers may occur depending on the sample (Merikangas et al 2007) Together with increasing evidence of an underlying genetic aetiology (Hayden and Nurnberger 2006) the relatively uniform epidemiological figures support, without neglecting ethnic and cultural diversity, that an optimised biological, mostly psychopharmacological, treatment may bring comparable benefits across cultures Despite this assumption, there are multiple guidelines and strategies for the treatment of bipolar I disorder worldwide which place different emphases on different kinds of treatments (Fountoulakis et al 2005) Although some may be due to biological diversities, much is due to different traditions in treatment and different attitudes towards particular agents and also the evidence upon which different approaches are based is limited or is subject to varying interpretation For the bipolar spectrum, treatment guidelines, when published, differ even more, since the nosological issue, especially the delineation from unipolar depression, is not conclusively settled (Benazzi 2007; Goodwin et al 2008) Given these diagnostic uncertainties and a lack of controlled evidence for treatment of the bipolar spectrum, all current guidelines, including this one, concentrate on Bipolar I disorder; if evidence is available, some more recent guidelines also include recommendations on the treatment of bipolar II disorder Despite all these limitations, guidelines appear quite welcome to clinicians According to a recent census by Perlis (Perlis 2007), 64% of those who responded said that they make regular use of them when making treatment decisions Diagnostic issues in bipolar I disorder In DSM-IV, bipolar I disorder is characterized by the occurrence of at least one manic or mixed episode The International Classification of Diseases, 10th ed (ICD-10, World Health Organization 1992) which is frequently used for clinical, but not Downloaded By: [World Federation of Societies of Biological Psychiatry] At: 11:39 19 May 2009 The WFSBP Guidelines for the Biological Treatment of Bipolar Disorders research purposes, however, does not separate between bipolar I and II disorder within the concept of bipolar disorder (F31), and requires at least two episodes (hypomania, mania, mixed state or depression) for the diagnosis If only a single manic episode has occurred, it is defined as separate category (F30) Almost all controlled clinical studies conducted after 1994 use categorical DSM-IV criteria for inclusion/exclusion of manic subjects, and as a consequence, evidence-based guidelines, including this one, are based on DSM-IV diagnostic entities However, since the definitions of mania within the DSM-IV and the ICD-10 are very similar (Licht et al 2001) guidelines on mania can be implemented into clinical settings using the ICD-10, at least when treating pure or psychotic mania Clinicians using the ICD-10 should be aware that the concept of mixed states in the ICD-10 is more loosely defined than in the DSM-IV According to the DSM-IV, mixed states imply that diagnostic criteria for a manic episode and a depressive episode (except for the duration criterion) are fulfilled simultaneously The concept of mixed mania (or dysphoric mania) is not well-defined, but sometimes used in the context of drug trials, referring to mania with some depressed features which are either not pronounced enough or insufficiently lasting enough to fulfil the criteria for a major depressive episode Tables I and II summarize DSM-IV diagnostic criteria for mania and mixed episodes However, the complexity of mania is not adequately captured by the DSM-IV Manic states are not uniform, nor they always fit in clear clinical distinctions Thus, a wide range of symptoms beyond the ones that defines the disorder may occur in an acute manic episode (see Table III) When additional psychotic symptoms are present, the manic episode or the mixed state are characterized as a psychotic mania or a psychotic mixed state, and this is considered a subtype, albeit on another level as the distinction between manic and mixed states It is unclear whether secondary grandiose delusions Á the commonest clinical manifestation of ‘‘psychosis’’ merits qualitative distinction since it looks much more like an expression of severity Of importance, first rank symptoms also occur in mania and may confuse the distinction from schizophrenia The separation between mood-congruent and mood-incongruent psychotic symptoms seems to be more relevant to prognosis than to treatment Finally, the task force is aware that there are even more manifestations of mania beyound DSM-IV and ICD-10 that are of clinical importance and should merit more attention in guidelines, e.g., mania with delirium, oligo-monosymptomatic forms of mania, chronic mania, and specific manifestations of mania 87 in senium and childhood However, controlled evidence for specific treatments is mostly lacking, and including all subtypes and manifestation of mania is virtually impossible for a comprehensive guideline Clinical experience with the various tentative antimanic agents over recent years has suggested that a drug that is efficacious in one subtype of mania is not necessarily the treatment of choice for the other subtypes Secondary (and often post-hoc) analyses of large randomized trials usually dealt with pure (or classical) mania versus mixed states, and distinguished between the presence and absence of a rapid cycling course In recognition of this available information, this guideline will, when data allow, also distinguish between pure mania, dysphoric mania and mixed states, psychotic mania, and, finally, hypomania Rapid cycling as a course specifier, however, will no longer receive special attention in this updated guideline for two reasons: rapid cycling appears not to be a distinct class on its own (Kupka et al 2005; Schneck et al 2008) and to date no firm evidence has been found that manic patients with rapid cycling respond differently in the short term to acute antimanic treatment compared to those without rapid cycling in the short term (Vieta et al 2004) Special treatment considerations depending on episode frequency are more important in treating bipolar depression (avoiding treatment emergent affective switches (TEAS)) and in the choice of maintenance treatment Methods These guidelines address the treatment of acute mania mainly in adults, although, when evidence was available, they also mention treatment options in adolescents and the elderly They are primarily based on evidence from randomised clinical studies, thereby adhering to the principles of evidence-based medicine The data used for these guidelines have been extracted from a MEDLINE and EMBASE search, the Science Citation Index at Web of Science (ISI) (all until end of 2008), from recent proceedings of key conferences, and from various national and international treatment guidelines A few additional trials were found by hand-searching in text books In addition, www.clinicaltrials.gov was accessed to check for unpublished studies Categorization of efficacy and recommendations derived from the evidence are, whenever available, based on studies that fulfilled certain methodological requirements, including standard diagnostic criteria, adequate sample size, use of a control group, randomization to treatment, double-blind conditions, valid and sensitive psychometric rating scales 88 H Grunze et al Downloaded By: [World Federation of Societies of Biological Psychiatry] At: 11:39 19 May 2009 Table I Diagnostic criteria for acute mania according to DSM-IV Criteria for Manic Episode (DSM-IV, p 332) j A A distinct period of abnormally and persistently elevated, expansive, or irritable mood, lasting at least week (or any duration if hospitalization is necessary) j B During the period of mood disturbance, three (or more) of the following symptoms have persisted (four if the mood is only irritable) and have been present to a significant degree:  Inflated self-esteem or grandiosity  Decreased need for sleep (e.g., feels rested after only hours of sleep)  more talkative than usual or pressure to keep talking  flight of ideas or subjective experience that thoughts are racing  distractibility (i.e., attention too easily drawn to unimportant or irrelevant external stimuli)  increase in goal-directed activity (either socially, at work or school, or sexually) or psychomotor agitation  excessive involvement in pleasurable activities that have a high potential for painful consequences (e.g., engaging in unrestrained buying sprees, sexual indiscretions, or foolish business investments) j C The symptoms not meet criteria for a Mixed Episode j D The mood disturbance is sufficiently severe to cause marked impairment in occupational functioning or in usual social activities or relationships with others, or to necessitate hospitalization to prevent harm to self or others, or there are psychotic features j E The symptoms are not due to the direct physiological effects of a substance (e.g., a drug of abuse, a medication, or other treatments) or a general medical condition (e.g., hyperthyroidism) and appropriate statistical tests, fulfilment of good clinical practice (GCP) criteria, and approval by properly-constituted ethics committee Unfortunately, abstracts of some recent key studies which have been presented as posters so far not supply all these information In these instances, additional information was requested from the sponsoring companies of these studies When randomised, double-blind trials were not available, other sources of information such as open studies and case reports have also been collected The results of metanalyses had been used only to a minor extent Generally, meta-analyses mostly exist for groups of drugs, but not for every single drug and intervention Moreover, meta-analyses have a number of methodological shortcomings, which can make their conclusions less reliable than those of the original studies (Anderson 2000; Bandelow et al 2008) For acute mania, some methodologically sound metaanalyses are available (e.g., Scherk et al 2007; Smith et al 2007b), limiting individual study inclusion to trials meeting rigorous criteria With that level of individual study input, some useful comparative efficacy and tolerability analyses and effect size comparisons are feasible both for drug vs placebo and for individual drugs vs lithium, the most frequently used main active comparator, become possible and effect size comparisons are feasible Even metanalyses carry the risk of over- powering, i.e finding a difference to placebo that may be statistically, but not clinically significant, the increase of power may be useful in answering important secondary clinical questions about subgroups As an additional source of information, other guideline activities published after the first edition of this guideline (Grunze et al 2003a) were also considered (Zarin et al 2002; Licht et al 2003; Royal Australian and New Zealand College of Psychiatrists Clinical Practice Guidelines Team for Bipolar Disorder 2004; National Collaborating Centre for Mental Health 2006; Yatham et al 2006; Jon et al 2008; Nolen et al 2008) In contrast with the preceding WFSBP Bipolar Mania guidelines (Grunze et al 2003a), but in line with the bipolar depression (Grunze et al 2002) and maintenance treatment guideline (Grunze et al 2004), this update is structured in terms of groups of medication rather than by subtypes of mania, although summaries on treatment of subtypes are provided in the end of the paper In order to achieve uniform and, in the opinion of this taskforce, appropiate ranking of evidence we adopted the same hierarchy of evidence based rigor and level of recommendation as was published recently in the WFSBP Guidelines for the Pharmacological Treatment of Anxiety, Obsessive-Compulsive and Post-Traumatic Stress Disorders (Bandelow Table II Diagnostic criteria for a mixed episode according to DSM-IV A The criteria are met both for a Manic Episode and for a Major Depressive Episode (except for duration) nearly every day during at least a 1-week period B The mood disturbance is sufficiently severe to cause marked impairment in occupational functioning or in usual social activities or relationships with others, or to necessitate hospitalization to prevent harm to self or others, or there are psychotic features C The symptoms are not due to the direct physiological effects of a substance (e.g., a drug of abuse, a medication, or other treatment) or a general medical condition (e.g., hyperthyroidism) The WFSBP Guidelines for the Biological Treatment of Bipolar Disorders Table III Frequency of symptoms observed clinically during acute manic episodes (adapted from Goodwin and Jamison (2007) Downloaded By: [World Federation of Societies of Biological Psychiatry] At: 11:39 19 May 2009 Symptom Weighted mean (%) Mood symptoms Irritability Euphoria Depression Lability Expansiveness 71 63 46 49 60 Cognitive symptoms Grandiosity Flight of ideas, racing thoughts Distractibility, poor concentration Confusion 73 76 75 29 Psychotic symptoms Any delusions Grandiose delusions Persecutory/paranoid delusions Passivity delusions Any hallucinations Auditory hallucinations Visual hallucinations Olfactory hallucinations 53 31 29 12 23 18 12 15 Presence or history of psychotic symptoms Thought disorder First rank Schneiderian symptoms 61 19 18 Activity and behaviour during mania Hyperactivity Decreased sleep Violent, assaultive behavior Rapid, pressured speech Hyperverbosity Nudity, sexual exposure Hypersexuality Extravagance Religiosity Head decoration Regression (pronounced) Catatonia Fecal incontinence (smearing) 90 83 47 88 89 29 51 32 39 34 28 24 13 et al 2008) (See Table IV) The WFSBP Anxiety guideline supplies a detailed rational for choosing the different levels of evidence and derived recommendations In brief, a drug must have shown its efficacy in double-blind placebo-controlled studies in order to be recommended with substantial confidence (Categories of evidence (CE) A or B, recommendation grades 1Á3) Depending on the number of positive trials and the absence or presence of negative evidence, different categories of evidence for efficacy are assigned A distinction was also made between ‘‘lack of evidence’’ (i.e studies proving efficacy or non-efficacy not exist) and ‘‘negative evidence’’ (i.e the majority of controlled studies shows non-superiority to placebo or inferiority to a comparator drug) When there is lack of evidence, a drug could still reasonably be tried in a patient unresponsive to standard treatment, while such an 89 attempt should not be undertaken with a drug that showed negative evidence Recommendations were then derived from the category of evidence for efficacy (CE) and from additional aspects as safety, tolerability and interaction potential (in the body of text summarized under the heading ‘‘effectiveness’’) The recommendation grades (RG) can be viewed as steps: Step would be a prescription of a medication with RG When this treatment fails, all other Grade options should generally be tried first before switching to treatments with RG 2, then 3, and In some cases, e.g., the combination of an RG and an RG option can preferentially be tried instead of combining two RG options We have not considered the direct or indirect costs of treatments as these vary substantially across different health care systems Additionally, some of the drugs recommended in this guideline may not (or not yet) have received approval for the treatment of mania in every country As the approval by national regulatory authorities is dependent on a variety of factors, including the sponsor’s commercial interest (or lack thereof) this guideline is exclusively based on the available evidence Large placebo-controlled studies include subjects with a variety of severity grades of mania above a predefined threshold (usually a YMRS (Young et al 1978) score of ]20 or a SADS-CÁderived Mania Rating Scale (MRS) (Endicott and Spitzer 1978) of ]14 in monotherapy studies; in adjunctive, placebocontrolled trials also lower inclusion scores have been used, e.g., YMRS score ]16) Mean baseline scores for YMRS ratings are mostly between 28 and 32 (corresponding to moderate to severe mania), but with a large standard deviation Unless specific subanalyses have been made, the results not allow conclusions about efficacy in very severe mania or, conversely, mild mania Thus, when grading evidence for efficacy, any grading refers somewhat artificially to ‘‘moderate’’ mania, which represents a mean of all single scores, but is not a homogeneous group If specific positive or negative evidence exists for severe mania or psychotic mania, either by subanalyses of patient groups or specific trials, this information is also provided Furthermore, most RCTs in acute mania have a duration of weeks, and only more recently double-blind extension periods up to 12 weeks had been added to the protocols Thus, the clinically important question of maintenance of effect could not be considered as a core criterion for efficacy The task force is aware of several inherent limitations of these guidelines When taking negative evidence into consideration, we rely on their publication or their presentation or the willingness of study 90 H Grunze et al Table IV Categories of evidence (CE) and recommendation grades (RG) Category of Evidence A Description Full evidence from controlled studies is based on: two or more double-blind, parallel-group, randomized controlled studies (RCTs) showing superiority to placebo (or in the case of psychotherapy studies, superiority to a ‘‘psychological placebo’’ in a study with adequate blinding) and one or more positive RCT showing superiority to or equivalent efficacy compared with established comparator treatment in a three-arm study with placebo control or in a well-powered non-inferiority trial (only required if such a standard treatment exists) Downloaded By: [World Federation of Societies of Biological Psychiatry] At: 11:39 19 May 2009 In the case of existing negative studies (studies showing non-superiority to placebo or inferiority to comparator treatment), these must be outweighed by at least teo more positive studies or a meta-analysis of all available studies showing superiority to placebo and non-inferiority to an established comparator treatment Studies must fulfill established methodological standards.The decision is based on the primary efficacy measure B Limited positive evidence from controlled studies is based on: one or more RCTs showing superiority to placebo (or in the case of psychotherapy studies, superiority to a ‘‘psychological placebo’’) or a randomized controlled comparison with a standard treatment without placebo control with a sample size sufficient for a non-inferiority trial and In the case of existing negative studies (studies showing non-superiority to placebo or inferiority to comparator treatment), these must be outweighed by at least one more positive study or a meta-analysis of all available studies showing superiority to placebo or at least one more randomized controlled comparison showing non-inferiority to an established comparator treatment C C1 C2 C3 Evidence from uncontrolled studies or case reports/expert opinion Uncontrolled studies is based on: one or more positive naturalistic open studies (with a minimum of evaluable patients) or a comparison with a reference drug with a sample size insufficient for a non-inferiority trial and no negative controlled studies exist Case reports is based on: one or more positive case reports and no negative controlled studies exist Based on the opinion of experts in the field or clinical experience D Inconsistent results Positive RCTs are outweighed by an approximately equal number of negative studies E Negative evidence The majority of RCTs studies or exploratory studies shows non-superiority to placebo (or in the case of psychotherapy studies, superiority to a ‘‘psychological placebo’’) or inferiority to comparator treatment F Lack of evidence Adequate studies proving efficacy or non-efficacy are lacking Recommendation Grade (RG) Based on: Category Category Category Category Category A evidence and good risk-benefit ratio A evidence and moderate risk-benefit ratio B evidence C evidence D evidence sponsors to supply this information Thus, this information may not always be complete and may bias evidence of efficacy in favour of a drug where access to such information is limited However, this potential bias has been minimized as much as possible by checking the www.clinicaltrials.gov database Another methodological limitation is sponsor bias (Lexchin et al 2003; Perlis et al 2005; Heres et al Downloaded By: [World Federation of Societies of Biological Psychiatry] At: 11:39 19 May 2009 The WFSBP Guidelines for the Biological Treatment of Bipolar Disorders 2006; Lexchin and Light 2006) inherent in most single studies on which the guidelines are based Also, all recommendations are formulated by experts who may try their best to be objective but are still subject to their individual pre-determined attitudes and views for or against particular choices Therefore, no review of evidence and guideline can in itself be an absolutely balanced and conclusive piece of evidence, but should direct readers to the original publications and, by this, enhance their own knowledge base Finally, the major limitation of any guideline is defined by the limitations of evidence One of the most important clinical questions that can not be sufficiently answered in an evidence based way is what to when any first step treatment fails, which happens in up to 50% of cases Therefore, with the current level of knowledge we can only provide suggestive guidelines and not rigorous algorithms Once a draft of this guideline had been prepared by the Secretary and Chairmen of the Task Force, it was sent out to the 53 members of the WFSBP Task Force on Treatment Guidelines for Bipolar Disorders for critical review and addition of remarks about specific treatment peculiarities in their respective countries A second draft, revised according to the respective recommendations, was then distributed for final approval These guidelines were established without any financial support from pharmaceutical companies Experts of the task force were selected according to their expertise and with the aim to cover a multitude of different cultures Lithium and anticonvulsants Traditionally, lithium and some anticonvulsants, mainly valproate and carbamazepine, have been grouped together as so called ‘‘mood stabilizers’’ in order to differentiate their broader, both acute and prophylactic action from the notionally limited acute antimanic effect of some typical neuroleptics, e.g., chlorpromazine and haloperidol Also, the term has implied that both mania and depression potentially were ameliorated However, with the emergence of atypical antipsychotics, some of them showing both acute and long-term efficacy, and others also having antidepressant efficacy, these agents could also be characterized as ‘‘mood stabilizers’’ As a consequence, we will avoid using the term ‘‘mood stabilizer’’ for lithium and anticonvulsants, since it may imply an artificial distinction between these substances and the atypical antipsychotics However, it remains appropriate to summarize the evidence on lithium and anticonvulsants under a single heading in the light both of 91 clinical tradition and of other aspects such as their potentially shared intracellular mechanisms of action and their continuous high ranking as a primary choice for maintenance treatment Lithium Efficacy To date a total of 29 published or presented studies have evaluated the acute antimanic efficacy of lithium Lithium therefore has clearly the largest pool of studies Four early studies, starting with Schou’s evaluation from 1954 (Schou et al 1954), tested lithium against placebo However, only more recent studies, starting with a threearm study comparing valproate and lithium against placebo (Bowden et al 1994) can be considered to fulfil current methodological standards for a drug approval study In the latter study, both lithium and valproate were significantly more effective than placebo Subsquently, lithium has also been employed as an internal comparator in other phase III approval studies, thus allowing a judgement of its efficacy Lithium was superior to placebo in a study with quetiapine as investigational drug (Bowden et al 2005), in two studies with topiramate as investigational drug (Kushner et al 2006), and in one study with aripiprazole as investigational drug (Keck et al 2007) In two studies with lamotrigine as investigational drug (GlaxoSmithKline study SCA 2008 and SCA 2009, unpublished) lithium did separate numerically, but not significantly from placebo However, one of the studies (SCA 2008) was not powered to show such a difference; in the other, lithium just missed significance at P 00.05 in the LOCF analysis of the primary outcome, the MRS-11 (Endicott and Spitzer 1978) In other methodologically less sophisticated comparator studies without a placebo arm, the antimanic efficacy of lithium was tested versus various antipsychotics (a total of 11 studies versus chlorpromazine and/or haloperidol (Grunze 2003), one versus zuclopenthixol (Gouliaev et al 1996), two versus olanzapine (Berk et al 1999; Niufan et al 2008), one against risperidone (Segal et al 1998), one against verapamil (Walton et al 1996) one against clonazepam (Clark et al 1997), one against lamotrigine (Ichim et al 2000) and five versus carbamazepine (Placidi et al 1986; Lerer et al 1987; Lusznat et al 1988; Okuma et al 1990; Small et al 1991) The response rates given for lithium in randomised studies (whereby different treatment duration and responder criteria were applied from study to study) range from 32% (Small et al 1991) to 94% (Freeman et al 1992) which may also reflect the different severities of mania in these studies For example, in the study of Prien et al (1972) lithium Downloaded By: [World Federation of Societies of Biological Psychiatry] At: 11:39 19 May 2009 92 H Grunze et al did not perform as well as chlorpromazine in the subgroup of highly agitated patients A recent metaanalysis of six randomized, controlled trials with lithium in acute mania (four of them published: Bowden et al 1994, 2005; Kushner et al 2006), and two as part of a registration dossier (SCA 2008 and SCA 2009) revealed an overall standardized effect size of 0.40 [95% confidence interval (CI): 0.28, 0.53] and an overall NNT (‘‘numbers-needed-to treat’’) for response of (95% CI: 4, 13) (Storosum et al 2007) As to the efficacy of lithium in psychotic mania, earlier comparative studies indicated that it was more the degree of severity than the presence of psychotic symptoms that was associated with a poorer response to lithium (compared to a typical neuroleptic) (Licht 2006) In the study comparing quetiapine with placebo, using lithium as internal comparator (Bowden et al 2005), it was reported that quetiapine and lithium did equally well (and superior to placebo) in terms of reduction in the PANSS positive subscale scores Also a post-hoc analysis analysis of data from the valproateÁlithiumÁ placebo trial by Bowden et al (Bowden et al 1994) found similar responses to lithium and valproate in a subgroup of psychotic patients (Swann et al 2002) Protocol-defined target plasma levels for lithium in recent controlled studies were usually in the range between 0.6 and 1.3 mmol/l In clinical practice, adolescents and young adults may require and tolerate at the higher end of this range, whereas elderly patients may tolerate only dosages at the lower end of this range Lithium is available in different salt preparations, e.g., lithium carbonate, lithium citrate and lithium sulfate There is no evidence for different efficacy between these salts However, lithium carbonate and lithium citrate are also available as extended release preparation, which may have advantages for tolerability Effectiveness The usefulness of lithium in acute mania may be limited by the need for regular plasma level checks to avoid toxicity, as well as by its side effect profile and contraindications These limitations have been dealt with extensively in textbooks (Goodwin and Jamison 2007) and reviews (McIntyre et al 2001) A slower onset of action of lithium, relative to the investigational drug, has been observed in some controlled studies (e.g., Keck et al 2007), but not in others (e.g., Bowden et al 1994, 2005) Recommendation Based on the available studies, lithium falls into CE for antimanic efficacy ‘‘A’’.1 Efficacy may be more pronounced in pure (euphoric) mania than in mania with concomitant dysphoric or depressive features (Swann et al 1997) However, its potentially slower onset of action together with the low level of sedative properties often makes it necessary to combine it with a tranquilizing agent at treatment initiation In addition, regular plasma level monitoring is essential due to its relative small safety margin Although not absolutely contraindicted, lithium is rarely suitable in certain medical conditions, which therefore should be excluded before treatment initiation, e.g., renal problems or thyroid dysfunction In these instances, regular medical checkups are mandatory With this reduced practicability, the RG would be ‘‘2’’2 for the solely acute use of lithium If considerations of maintenance treatment play an additional role at the time of acute treatment initiation, lithium alone or in combination may become the primary choice (RG’’1’’) already at this early stage Carbamazepine Efficacy Starting with the first studies of Okuma et al (1973), the efficacy of carbamazepine for the acute treatment of mania has been demonstrated in several small studies, both by Okuma’s group and by other investigators (e.g., Ballenger and Post 1980; Muă ller and Stoll 1984; Emrich et al 1985; Post et al 1987) Comparative studies have been conducted with both typical neuroleptics, lithium and with valproate (Okuma et al 1979; Klein et al 1984; Placidi et al 1986; Stoll et al 1986; Lerer et al 1987; Lusznat et al 1988; Brown et al 1989; Okuma et al 1990; Small et al 1991; Vasudev et al 2000) The impression of these studies was that carbamazepine was overall equally effective as comparators, with a probably slightly slower onset of response compared to neuroleptics (Brown et al A: Full evidence from controlled studies is based on: two or more double-blind, parallel-group, randomized controlled studies (RCTs) showing superiority to placebo (or in the case of psychotherapy studies, superiority to a ‘‘psychological placebo’’ in a study with adequate blinding) and one or more positive RCT showing superiority to or equivalent efficacy compared with established comparator treatment in a three-arm study with placebo control or in a well-powered non-inferiority trial (only required if such a standard treatment exists) In the case of existing negative studies (studies showing non-superiority to placebo or inferiority to comparator treatment), these must be outweighed by at least two more positive studies or a meta-analysis of all available studies showing superiority to placebo and non-inferiority to an established comparator treatment Studies must fulfill established methodological standards.The decision is based on the primary efficacy measure Recommendation Grade corresponds to ‘‘Category A evidence and moderate risk-benefit ratio’’ Downloaded By: [World Federation of Societies of Biological Psychiatry] At: 11:39 19 May 2009 The WFSBP Guidelines for the Biological Treatment of Bipolar Disorders 1989) and valproate (Vasudev et al 2000), but slightly faster acting than lithium (Small et al 1996) The first large randomized, placebo controlled mania study with carbamazepine as investigational drug was not published until 2004 (Weisler et al 2004b) Both this study and a replication study (Weisler et al 2005) showed significant superiority of carbamazepine over placebo in the treatment of acute mania Looking into specific sub-groups of patients, carbamazepine may be helpful in patients with incomplete response to lithium (or presumably other agents as well) in acute mania (Lerer et al 1987; Post et al 1987; Okuma et al 1990), in patients with co- morbid organic (neurological) disorders (Schneck 2002) and schizoaffective patients (Goncalves and Stoll 1985; Elphick 1985) Effectiveness Common side effects of carbamazepine include oversedation and blurred vision, especially with high dosages and rapid titration Rare, but potentially severe side effects include allergic reactions, lupus erythematosus, agranulocytosis and hyponatremia Tolerability isssues may be less problematioc with extended release formulations Detailed information on the tolerability and safety profile of carbamazepine is available in recent reviews and text books (Grunze and Walden 2002; Gajwani et al 2005; Grunze 2006) In addition, carbamazepine is associated with an increased risk of birth defects (Morrow et al 2006) Carbamazepine’s main shortcoming in routine use, however, is its capacity for interaction with other psychotropic medication, including several antipsychotics, antidepressants and anticonvulsants (Spina et al 1996) Since a majority of patients with acute mania may be on treatment with several medications (Wolfsperger et al 2007), this complicates and limits the utility of carbamazepine Recommendation Based on two double-blind, placebo-controlled studies and several comparator studies, with at least one of them (Okuma et al 1979) adequately powered to show non-inferiority, the CE for antimanic efficacy for carbamazepine is ‘‘A’’ The main short-comings of carbamazepine are some tolerability issues with rapid titration and its interaction potential with a variety of other psychiatric and non-psychiatric medication, including contraceptives, through enzymatic induction making it a RG ‘‘2’’ recommendation Valproate This guideline uses ‘‘valproate’’ as common generic name for the different preparations tested in acute 93 mania, e.g., valproic acid, sodium valproate, divalproate, divalproex sodium, and valpromide As far as pharmacokinetics and pharmacodynamics are concerned, only valproic acid finally reaches and penetrates the blood-brain barrier Although tolerability is enhanced with extended release preparations, the difference does not warrant grouping valproic acid derivatives as different medications Efficacy The antimanic activity of valproate was first reported by Lambert et al (1966) Subsequently, the efficacy of valproate in the treatment of acute mania has been evaluated in short-term randomised controlled trials, both as monotherapy (Emrich et al 1980; Pope et al 1991; Bowden et al 1994, 2006) and in combination with a neuroleptic (Muă llerOerlinghausen et al 2000) These studies have provided consistent evidence that valproate is an efficacious treatment for acute mania (Macritchie et al 2003) Similar antimanic efficacy was observed for valproate in comparator trials with lithium (Freeman et al 1992; Bowden et al 1994, 2008) haloperidol (McElroy et al 1996a) and in one study against olanzapine (Zajecka et al 2002) but not in two others (Zajecka et al 2002; Tohen et al 2009b) Compared to carbamazepine (Vasudev et al 2000), valproate appeared superior in terms of overall outcome Based on secondary analyses from the comparative trials with olanzapine and the comparative trial with lithium and placebo by Bowden and co-workers (Bowden et al 1994; Swann et al 2002) and the study by McElroy et al (1996a) comparing valproate with haloperidol, albeit small in sample size, there are indications that valproate also works in psychotic mania Effectiveness In acute manic patients, dose-loading with 20Á30 mg/kg body weight seems to be more effective than slower titration schemes (Keck et al 1993; Grunze et al 1999; Hirschfeld et al 2003) Plasma levels of 75Á99 mg/l (520Á690 mmol/l) seem to be associated with the best efficacy/tolerability ratio (Keck et al 2005; Allen et al 2006) The tolerability of valproate appears fair across trials Gastointestinal discomfort, sedation and tremor are in most trials more frequently observed with valproate than with placebo, but usully not result in higher discontinuation rates For rare, but severe complications as thrombocytopenia, hepatic failure, pancreatitis or hyperammonaemic coma and precaution measures we refer to the pertinent reviews (e.g., Bowden and Singh 2005) Recommendation The CE for efficacy can be classified as ‘‘A’’ with comparable effect sizes for pure Downloaded By: [World Federation of Societies of Biological Psychiatry] At: 11:39 19 May 2009 94 H Grunze et al mania (with or without psychotic symptoms) and mania with dysphoric/depressive features The safety margin of valproate is relatively large allowing rapid titration (‘‘dose loading’’) and a subsequent earlier onset of action Valproate is not appropriate in some medical conditions, e.g., liver disease, and in combination with some medication, e.g., warfarin As these conditions can usually be ruled out clinically with a good degree of certainty, the RG would be ‘‘1’’ for the acute treatment of mania However, caution should be used in women of child-bearing age, not only because of teratogenicity and high risk of developmental delay (Viguera et al 2007), but also because of the supposed increased risk of a polycystic ovary syndrome (PCOS) (Soares 2000; Rasgon et al 2005) Thus, the RG for younger women is no more than‘‘2’’ Other anticonvulsants with potential antimanic properties Several other anticonvulsants have been poposed as having antimanic properties, but none of them has been studied enough to allow the conclusion that efficacy and tolerability were within the same range as the drugs previously reviewed in detail Additionally, for some, substantial evidence of marginal or unsatisfactory tolerability exists, and/or evidence of lack of difference from placebo is conclusive Thus, their RG is usually low and furthermore, they should not be considered as equal alternatives when other antimanic drugs fail to yield optimal outcomes Phenytoin has demonstrated antimanic properties in a small, double blind, placebo-controlled add-on study to haloperidol (Mishory et al 2000) (CE of efficacy ‘‘B3’’) The side effect profile of phenytoin, especially cognitive side effects and cerebellar atrophy (De Marcos et al 2003), however, makes it a medication of subordinate choice for acute mania (RG ‘‘3’’) Evidence for the antimanic properties of oxcarbazepine is not convincing (Hirschfeld and Kasper 2004); a recent review of several small, underpowered or placebo-uncontrolled studies came to the conclusion that it may be useful in treating manic symptoms (Popova et al 2007), but conclusive evidence is lacking (CE for efficacy ‘‘C1’’, RG ‘‘4’’) Due to the chemical resemblance with carbamazepine it is often assumed that it may be beneficial in patients who previously responded well to carbamazepine but had to discontinue it for reasons of tolerability or interaction with other medication Oxcarbazepine may also exhibit both interactions with other medications and tolerability issues, but to a lesser degree than carbamazepine; however, the risk of hyponatremia appears to be greater with oxcarbazepine Other anticonvulsants with CE of efficacy ‘‘C1’’4 include levetiracetam (Goldberg and Burdick 2002; Grunze et al 2003b; Kyomen 2006; Desarkar et al 2007) and zonisamide (Kanba et al 1994; McElroy et al 2005; Anand et al 2005) One small case series (Amann et al 2006) gives retigabine ‘‘C1’’ evidence The RG derived from these studies is ‘‘4’’ The CE for topiramate, gabapentin, and lamotrigine is ‘‘E’’5 (Ichim et al 2000; Pande et al 2000; Goldsmith et al 2003; Kushner et al 2006) and for pregabaline and tiagabine ‘‘F’’.6 In the case of tiagabine, open studies were suggestive of no efficacy together with an increased risk of epileptiform seizures (Grunze et al 1998; Suppes et al 2002) Atypical antipsychotics During recent years, the treatment portfolio of acute mania has significantly increased with the emergence of atypical antipsychotics For this article we list the different antipsychotics in alphabetical order within the group of atypical antipsychotics approved for mania, and within the group of atypical antipsychotics not yet approved or marketed Aripiprazole Efficacy Four placebo-controlled acute mania studies have been published or presented in scientific meetings as posters so far (Keck et al 2003a; Sachs et al 2006; Keck et al 2007; Young et al 2009) one of them including a lithium arm (Keck et al 2007) and B: Limited positive evidence from controlled studies is based on: one or more RCTs showing superiority to placebo (or in the case of psychotherapy studies, superiority to a ‘‘psychological placebo’’) or a randomized controlled comparison with a standard treatment without placebo control with a sample size sufficient for a non-inferiority trial or one or more sufficiently powered post-hoc analyses of RCTs showing superiority to placebo (or in the case of psychotherapy studies, superiority to a ‘‘psychological placebo’’) In the case of existing negative studies (studies showing non-superiority to placebo or inferiority to comparator treatment), these must be outweighed by at least one more positive study or a meta-analysis of all available studies showing superiority to placebo or non-inferiority to an established comparator treatment C1 evidence is based on: one or more positive naturalistic open studies (with a minimum of five evaluable patients or a comparison with a reference drug with a sample size insufficient for a non-inferiority trial and no negative controlled studies exist) E: The majority of RCTs studies or exploratory studies shows non-superiority to placebo (or in the case of psychotherapy studies, superiority to a ‘‘psychological placebo’’) or inferiority to comparator treatment F: Adequate studies proving efficacy or non-efficacy are lacking If existing, open studies or case reports showed a total lack of efficacy Downloaded By: [World Federation of Societies of Biological Psychiatry] At: 11:39 19 May 2009 102 H Grunze et al ECT in acute mania describes improvement in approximately 80% of patients (Mukherjee et al 1994), thus being greater than for any pharmacological intervention Retrospective comparison of ECT against several pharmacological interventions revealed similar efficacy of neuroleptics or lithium and ECT in mania (McCabe and Norris 1977b; Thomas and Reddy 1982) In another retrospective chart review, however, ECT outperformed lithium significantly (Black et al 1987) So far, there are only two prospective studies: One study compared initial ECT, followed by lithium continuation with lithium as exclusive treatment from initiation After weeks patients who had initially a course of ECT showed a significantly higher responder rate than those who started on lithium (Small et al 1988) In the other prospective study, combined treatment with ECT and chlorpromazine was more effective than chlorpromazine alone (Sikdar et al 1994) Recent work suggests that bifrontal ECT is at least as efficacious as bitemporal ECT in severe mania and better tolerated (Hiremani et al 2008; Barekatain et al 2008) Given the lack (and impracticality) of randomized, sham-controlled studies, the CE for ECT in acute mania is ‘‘C1’’, the RG ‘‘4’’ However, in the opinion of the WFSBP task force, ECT is still a valuable last resource in severe delirious mania which is otherwise treatment refractory (Karmacharya et al 2008) A possible alternative to ECT as a physical treatment, repetitive transcranial magnetic stimulation (rTMS) has not been shown to have unequivocal antimanic efficacy in a single blind study against sham-rTMS (Kaptsan et al 2003) (CE ‘‘E’’) Dosages and duration of treatment Recommended dosages for the different medication in monotherapy are given in Table V These dosages are derived from studies in acute mania They not necessarily reflect the whole dosage range that is approved for a given medication: dosages as supplied here are mostly in the upper approved dosage range In the case of combination treatment, a reduction of the daily dosage may be necessary when side effects of two medications are additive or potentiating Most combination treatment trials used lower dosage of the investigational drug than in the corresponding monotherapy studies However, in some instances, e.g., combination treatment with enzyme inducers like carbamazepine (Spina et al 1996), dosages of the investigational drug need a modest increase compared to monotherapy Therapeutic drug monitoring (TDM) is particularly advisable in patients who not respond to combination treatment regimens (Baumann et al 2004) Antimanic treatment has to be continued at least until full remission, syndromal and functional, has been achieved Persistence of subsyndromal mania is associated with a significantly increased risk of relapse (Tohen et al 2003d, 2006a) Most guidelines recommend continuation therapy for 6Á12 months after remission from an acute mood episode has been achieved; this recommendation is based upon evidence for unipolar depression, and controlled data in mania from discontinuation trials are only available for lithium (Goodwin 1994), olanzapine (Tohen et al 2006b) and aripiprazole (Keck et al 2006) supporting this approach with a grade ‘‘B’’ CE for these medications But for many substances, this recommendation is based upon expert advice and clinical reasoning (CE ‘‘C3’’) Also based on clinical experience, doses may me reduced at some point after remission has been achieved, depending on tolerability For lithium, this is mandatory for safety reasons, since the renal clearence of this agent diminish after an acute episode has resolved and since antimanic serum-levels in the continuation therapy may be too risky Therefore, based on these considerations, and unless there is doubt as to whether the manic episode may have had an external trigger, e.g., steroids, alcohol, other drugs of abuse, all patients should be offered continuation and maintenance regimens (for the indication, see (Grunze et al 2004)) Accordingly, in selection of a drug or regimen for treatment for acute mania an important consideration should be the overall efficacy and tolerability of the regimen in long term treatment, thereby minimizing switchs of medication which may be associated with an increased relapse risk Dealing with non-response Treatment should generally be initiated with a medication fulfilling the criteria for CE for efficacy ‘‘A’’ and having a RG of ‘‘1’’ (see Table V and Figure 1) If this first choice medication is inefficacious or leads only to partial response, it is unclear how long clinicians should wait before changing or amending medication In controlled studies, most successful investigational drugs start to separate from placebo within week Early partial response whether on active drug or placebo (Pappadopulos et al 2008), predicts later response at study endpoint However, detailed analyses on various response patterns are, so far, not available Response may be delayed with some medication that need titration (e.g., lithium and quetiapine) or are used in lower dosages (e.g., The WFSBP Guidelines for the Biological Treatment of Bipolar Disorders 103 Table V Categories of evidence (CE) and grade of recommendation (RG) for pharmacological and non-pharmacological treatments used in acute mania (in alphabetical order within one category of evidence) Downloaded By: [World Federation of Societies of Biological Psychiatry] At: 11:39 19 May 2009 Medication Category of evidence (CE) Recommendation Grade Aripiprazole Asenapine Carbamazepine Haloperidol Lithium Olanzapine Quetiapine Risperidone Valproate A A A A A A A A A 2 27 2 19 Ziprasidone Chlorpromazine Paliperidone Phenytoin Pimozide Tamoxifen Amisulpride Clonazepam Clozapine Levetiracetam Lorazepam Nimodipine Oxcarbazepine Retigabine Zonisamide Zotepine Verapamil Lamotrigine Topiramate Gabapentin Tiagabine Pregabalin ECT A B B B B B C1 C1 C1 C1 C1 C1 C1 C1 C1 C1 D E E E F F C1 110 3 3 4 4 4 4 4 Á Á Á Á Á rTMS E Typically recommended daily dose for adults (variations may occur due to different approvals) 1530 mg 10Á20 mg 600Á1200 mg (serum level 4Á15 mg/l) 5Á20 mg 600Á1200 mg (serum level 0.8Á1.3 mmol) 10Á20 mg8 400Á800 mg 2Á6 mg 1200Á3000 mg (loading dose 20Á30 mg/kg body weight; serum level 75Á100 mg) 80Á160 mg 300Á1000 mg 3Á12 mg; only 12 mg/d achieves ‘‘B’’ level 300Á400 mg 2Á16 mg 40Á80 mg 400Á800 mg 2Á8 mg 100Á300 mg 500Á1500 mg 4Á8 mg 240Á480 mg 900Á1800 mg 600Á1200 mg 100Á500 mg 200Á400 mg 480 mg 50Á200 mg 200Á600mg 900Á3600 mg 20Á40 mg 1800 mg Reserved for treatment refractory mania and special issues (e.g., as alternative option in pregnancy) Á If long-term treatment is considered at the same time, the RG for lithium is ‘‘1’’ A fixed dose of 20 mg olanzapine was sufficient to demonstrate significant antimanic effects in females with moderate to severe mania (Bech et al 2006) However, females achieve significantly higher plasma concentrations of olanzapine than males (Kelly et al 1999, 2006) This may imply that higer doses are needed in males with moderate to severe mania (Goodwin and Jamison 2007) Valproate is not recommended as first choice treatment (RG ‘‘1’’) in women of child-bearing age 10 The RG for ziprasidone is ‘‘2’’ in countries where its use is restricted due to regulatory order the first olanzapine monotherapy study: Tohen et al 1999) On the other hand, as acute mania constitutes a significant burden to patients and to everyone involved, clinicians may not want to wait for too long to tap the last potential of a medication Hence, in the absence of firm evidence, the task force recommends that a treatment trial should not last more than weeks Adressing what to next, in case of insufficient response after e.g., weeks, is also more based on expert opinion and clinical experience than driven by evidence The suggestion of the task force is that the continuation or discontinuation of a given initial antimanic treatment should be decided upon the basis of full, partial or no response (see Figure 1) However, it is an open question, whether an only partly sufficient treatment should be replaced by another treatment or whether another treatment should be added The latter approach can, besides assuming a synergistic effect, be justified as maximizing the likelihood of effect, since the first-line drug, albeit insufficient after the first weeks then still may have a chance to work on its own over time The former approach can be justified from a perspective on tolerability and by facilitating a proper monotharapy continuation therapy The use of standardized rating scales as the YMRS to determine and document is encouraged Clinical studies usually use a 50% reduction of the YMRS, MRS or MAS as response criterion (Goodwin and Jamison 2007): however, more detailed increments 104 H Grunze et al for partial response may be helpful in making clinical decisions (Tohen et al 2009a) Downloaded By: [World Federation of Societies of Biological Psychiatry] At: 11:39 19 May 2009 Monotherapy or combination treatment? In reality, less than 10% of acutely manic patients receive monotherapy; the avarage number of medication in acutely manic patients is apprpximately three (Wolfsperger et al 2007) Clinical routine appears to be based on polypharmacy in bipolar patients (Lin et al 2006; Ghaemi et al 2006; Wolfsperger et al 2007; Peh and Tay 2008) This underlines the difficulties in treating naturalistic samples compared to selected samples in clinical studies; less than 20% of a screened naturalistic patient cohort fulfills all inclusion criteria for entering a randomized, controlled trial (Licht et al 1997) Modifying factors mostly include comorbid conditions and severity of illness In line with this clinical practice are observations from randomized, controlled trials that addition of an antipsychotic drug to patients with persistent manic symptoms despite treatment with lithium or valproate has shown greater rates of acute efficacy than has continuation of lithium or valproate alone (Tohen et al 2002; Sachs et al 2002; Sachs et al 2004; Vieta et al 2009c): However, the obtainable clinical information from these trials are limited Firstly, there is no distinction between subjects responding insufficiently to an acute antimanic treatment with First choice medication: Choose monotherapy with a CE “A”, RG “1” medication, considering: • Symptoms of mania (e.g., euphoric, mixed, psychotic) and severity • Previous experience and patients prefernce • Evidence for efficacy as maintenance treatment if appropriate • Modifying medical factors and specific safety profile • Route and ease of administration • Tolerability and efficacy in continuation therapy if indicated Level Full response after weeks: Continue on medication until full remission as been achieved or beyond, if maintenance treatment is indicated Partial response after weeks: Continue on first choice medication, optimize dosage No response after weeks: switch to another first choice medication In severe mania: Consider combination Level If no further improvement is observed over the next three weeks, consider add-on treatment with another First choice medication If still unresponsive after weeks: Consider combination treatment with two First choice treatments Level If no or insufficient response: Exchange one medication (the potentially less effective for the actual symptoms) of the combined treatment against another CE “A” or “B” medication If insufficient or no response: • Restart at level or • Exchange one medication against another medication including CE “C” or “D” evidence, if appropriate or • In severe mania: consider clozapine or ECT Level Level Figure Treatment algorithm as suggested by the WFSBP taskforce CE, category of evidence; RG, recommendation grade (see Tables IV and V) Downloaded By: [World Federation of Societies of Biological Psychiatry] At: 11:39 19 May 2009 The WFSBP Guidelines for the Biological Treatment of Bipolar Disorders lithium or valproate and subjects suffering from a break-through mania with ongoing prophylactic treatment Secondly, clear and valid definitions and assessments of insufficient response are often lacking As to the important clinical question whether an antipsychotic and lithium (or valproate) combined from the beginning (a de novo combination) are better than the antipsychotic or the lithium or valproate given alone there is very limited data Actually, only the risperidone trial (Sachs et al 2002) gave to some extens such information, indicating that the de novo combination did not better than the lithium or valproate alone However, Muă ller-Oerlinghausen et al (2000) showed that valproate added to a typical neuroleptic (mainly haloperidol) is superior to the neuroleptic given alone in severely ill patients, most of them probably receiving the combination from the beginning A greater efficacy of combination treatment is also supported by a meta-analysis of Smith et al (2007a) Eight eligible add-on studies were included with a total of 1124 subjects Significant reductions in YMRS scores were demonstrated for haloperidol, olanzapine, risperidone and quetiapine as co-therapy compared with monotherapy with lithium or valproate For atypical antipsychotics combined, the pooled difference in mean scores was 4.41 (95% CI: 2.74, 6.07) In addition, significantly more participants on co-therapy met the response criterion (at least 50% reduction in YMRS score, RR 1.53 (1.31, 1.80)) However, this metaanalysis again mingles trials with de novo combinations and addon combination in insufficiently responsive patients Taken together, there is not enough unambiguous evidence that supports combination therapy as a general first line treatment Additionally, safety and practicability issues would clearly favour monotherapy as first line approach making best use of the dosage range available for a given medication Combined treatments are potentially associated with higher frequency or greater severity of side effects (Smith et al 2007a; Vieta et al 2008) putting patients at a potentially unnecessary risk and perhaps disrupting the therapeutic alliance A recent guideline (Yatham et al 2006) recommend combination treatment as a possible first line choice (not restricted a special grade of severity of mania); however, the WFSBP task force feels that clinicians in general should be encouraged to make best use of a diligently chosen monotherapy before switching to combinatons in order to minimize side effects and medical risks Monotherapy should be the primary choice at least in mild and moderate mania; although polytherapy has proven to be potentially more efficacious in certain combinations (atypical 105 antipsychotic'lithium or valproate vs lithium or valproate alone) it should be reserved for severe mania or as a subsequent step in mild and moderate mania after switching (unsuccessful) medication How antimanics compare? Direct comparative trials between these antimanic substances are still limited, especially between different atypicals, the one exception being olanzapine vs risperidone (Perlis et al 2006a) Others are either inconclusive (olanzapineÁvalproate (Zajecka et al 2002; Tohen et al 2003b; Tohen et al 2009b), aripiprazoleÁhaloperidol (Vieta et al 2005a)), not powered for comparing investigational drug and comparator, or the relevant statistical comparison has not been made (the various studies using lithium as comparator, or olanzapine as comparator for asenapine (Hirschfeld et al 2007)) There are three exceptions, showing that haloperidol is more powerful in the short term treatment of acute mania than olanzapine (Tohen et al 2003a), quetiapine (McIntyre et al 2005) and aripiprazole (Young et al 2009) (see also Scherk et al 2007) Comparison of atypicals across trials, however, did not hint towards pronounced differences in efficacy (Perlis et al 2006b) Although haloperidol may be more powerful than some atypicals, but is still a RG ‘‘2’’ medication, as the use of typical neuroleptics in higher dosages should be restricted to emergencies where parenteral administration is the only choice, and should be limited to a maximum of a few weeks, to avoid the risk of tardive dyskinesia (TD) (Kasper et al 2006) TD may have an increased incidence in bipolar patients (Hamra et al 1983; Mukherjee et al 1986; Kane 1999) The aetiology of TD remains uncertain but is believed to result from long-term blockade of dopamine receptors The true risks for atypical antipsychotics with a high degree of D2 receptor occupancy are not yet firmly established, but appear lower (Remington 2007) The key message from the introduction of the atypical drugs is that it is possible to achieve antipsychotic and anti-manic action without inducing severe extra-pyramidal side effects This may imply that low-dose typical neuroleptics are still a reasonable alternative to atypical antipsychotics in selected patients (Geddes et al 2000; Lieberman et al 2005) This may apply as much to mania as to schizophrenia In this respect, it has also beeen demonstrated that chlorpromazine is more powerful in excited manic patients than lithium (Prien et al 1972) Taken together, the choice of the primary treatment depends mainly on previous responsiveness, 106 H Grunze et al patient’s preference, safety and tolerability profile, including medical conditions or co-medication that may interfere with the chosen drug, route of administration and future need of maintenance treatment Special considerations for treatment depending on the subtype of mania Downloaded By: [World Federation of Societies of Biological Psychiatry] At: 11:39 19 May 2009 Dysphoric mania and mixed states These two manifestations of mania are summarised under one heading According to DSM-IV, mixed states imply that diagnostic criteria for a manic episode and a depressive episode (except for the duration criterion) are fulfilled simultaneously Dysphoric mania describes mania with some depressed and dysphoric features that are either not pronounced enough or insufficiently lasting enough to fulfil the criteria for a major depressive episode (see also section on Diagnostic issues in bipolar I disorder) Women appear more often affected than men, both in bipolar I (Arnold et al 2000) and II disorder (Suppes et al 2005) As dysphoric (or mixed) mania and mixed states have not been the subject of intensive primary studies and prospective controlled trials so far, we have only a limited amount of evidence for efficacy and even less for the superiority of one drug over another Another issue is that when antimanic efficacy has been indicated in mixed states, this does not necessarily imply efficacy on depressive symptoms and may be far from efficacy on core depressive symptoms In fact, depression rating scales usually used in clinical trials also capture some manic symptoms Secondary analysis of the influential valproate efficacy study (Swann et al 1997) as well as some older studies (Himmelhoch and Garfinkel 1986; Secunda et al 1987) indicated that lithium may not be very effective, and that valproate, carbamazepine, olanzapine and risperidone may be more efficacious than lithium in these patients (Freeman et al 1992; Swann et al 1997; Goldberg and Harrow 1998; Tohen et al 2000; Benabarre et al 2001) Post hoc analyses of the pivotal phase III studies with olanzapine (Baker et al 2003), ziprasidone (Vieta 2005; Greenberg and Citrome 2007) and aripiprazole (Sachs et al 2006) demonstrated comparable efficacy for mixed states and pure mania In contrast, the evidence for risperidone and carbamazepine is mostly based on open studies Although there is no direct evidence for lack of efficacy, the use of typical neuroleptics (especially in higher dose) may exacerbate dysphoric or depressive symptoms and should probably be avoided (Whitlock and Evans 1978; Tohen et al 2003a) Psychotic mania Psychotic mania has only recently been designated as a subtype of bipolar mania It is unclear whether secondary grandiose delusions Á the commonest clinical manifestation of ‘‘psychosis’’ merits qualitative distinction since it looks much more like an expression of severity On the other hand, first rank symptoms also occur in mania and confuse the distinction from schizophrenia ‘‘Psychotic mania’’ is a diagnosis that conflates these perhaps different clinical conditions Psychotic mania has been so little studied in clinical trials that recommendations regarding drug regimens are based principally on inferential criteria Typical neuroleptics, in this case pimozide, may be superior to lithium as shown by the Northwick Park functional psychosis study (Johnstone et al 1988) (CE ‘‘B’’, RG ‘‘3’’) However, this may not be directly related to their antipsychotic properties, but to greater efficacy in severe manic states which are regularly accompanied by psychosis (Licht 2006) Some older guidelines also favoured anticonvulsants over lithium when psychotic symptoms are present, e.g., (Kusumakar et al 1997), others recommended the combination of either valproate or lithium with an antipsychotic right from the start (McElroy et al 1996b) In the single randomized comparison of two efficacious drugs in a sample of patients with acute psychotic mania valproate and haloperidol were similarly efficacious Limitations of the study included an open design and a small sample ((McElroy et al 1996a), CE ‘‘C1’’, RG ‘‘4’’) With the emergence of atypical antipsychotics, monotherapy options may increase, but unambiguous prospective, controlled trials are still lacking However, post hoc analysis of Phase III studies of olanzapine, risperidone and ziprasidone showed similar response rates in psychotic versus nonpsychotic mania Severity of mania Recent treatment recommendations have almost uniformly advocated the preferential use of lithium, valproate (‘‘mood stabilisers’’) or atypical antipsychotics for the first-line treatment of mania Despite this, typical neuroleptics are still very widely used in manic patients (Tohen et al 2001; Wolfsperger et al 2007) As long as care is taken to avoid EPS, long experience supports this strategy, even if formal controlled evidence for the group of most severe manic patients is limited However, as outlined previously, haloperidol is usually not considered a first line drug for tolerability reasons Randomised studies comparing atypicals with the typical neuroleptic haloperidol were conducted without specification of severity of mania as long as the inclusion Downloaded By: [World Federation of Societies of Biological Psychiatry] At: 11:39 19 May 2009 The WFSBP Guidelines for the Biological Treatment of Bipolar Disorders threshold was achieved, and supplied varying results (Smulevich et al 2005; McIntyre et al 2005; Vieta et al 2005a; Young et al 2009) It is, however, noteworthy that a retrospective chart review of manic patients in a hospital setting showed advantages of atypical antipsychotics over typical neuroleptics (Letmaier et al 2006) Obviously, the severity of behavioural disturbance is also an important factor in deciding on first-line treatment in acute mania Most treatment algorithms are based on controlled trials in moderately manic patients who are still able to give informed consent In clinical practice, severity of mania and speed of onset of action are the primary arguments in favour of a particular drug In the ultra-short treatment of acutely manic and highly excited or violent patients, typical neuropleptics still have their place (Cipriani et al 2006) and are superior to lithium (Prien et al 1972; Garfinkel et al 1980) and some atypical antipsychotics (Scherk et al 2007) In patients who are severely manic but still willing to take medication, loading with valproate (Hirschfeld et al 1999) or carbamazepine (Dose and Emrich 1995) may be alternatives, whereas lithium loading is effective (Keck et al 2001), but associated with higher risks of accidental overdosing Recent trials in severly manic patients, e.g., a randomized, controlled trial with risperidone (Khanna et al 2005), and post hoc subgroup analyses of severly manic patients in randomized, controlled trials with other atypical antipsychotics support the usefulness of risperidone, ziprasidone, aripiprazole and olanzapine in this patient group Clozapine has also shown efficacy in refractory mania, both euphoric and dysphoric, in open prospective trials (CE C1) (Muă ller and Heipertz 1977; Suppes et al 1992; Antonacci and Swartz 1995; Calabrese et al 1996; Green et al 2000) Finally, the efficacy of electroconvulsive therapy in severe and delirious manic states is supported by numerous case series (CE ‘‘C1’’) (Grunze and Scharfetter 2004) Hypomania Hypomania may be known to be the prelude to fullblown mania in individual patients, in which case treatment should be as for mania Otherwise hypomania is not a common point for the initiation of new treatment In case the patient is receiving prophylactic treatment with an antimanic agent, the best recommendation is to check the plasma level of the medication and, depending on the result, increase the dosage If the patient is not currently receiving an antimanic medication, an appropriate drug could be introduced that should, if indicated, also be the drug of choice for prophylaxis 107 It is unclear whether the controlled positive results for olanzapine and valproate in mild to moderate mania (Tohen et al 2009b) can be extrapolated to hypomania In addition, there is some uncontrolled evidence for the usefulness of risperidone in hypomania (Vieta et al 2001) If no further prophylaxis is planned, short-term treatment with either valproate or an atypical antipsychotic may be the best choice (CE ‘‘C3’’), as both are well tolerated, have a good safety profile and a relatively rapid onset of action, minimising the danger that hypomania develops into mania within the next days In this respect, it is also important to intervene early against sleep loss as this may be an important factor for developing full blown mania In contrast to more severe manic states, hypomania may be still manageable to some extent by behavioural interventions in combination with pharmacotherapy These inventions may center around modifications of daily routines, e.g., maintaining a natural sleep wake cycle, stress avoidance, and some elements of cognitive behavioural therapy (CBT) (Basco and Rush 1996) However, so far no psychological intervention has shown efficacy in controlled studies in comparison to a ‘‘placebo’’ intervention in mania (Gutierrez and Scott 2004) The domain of psychotherapy in bipolar disorder largly remains in bipolar depression and relapse preventiona Future perspectives The treatment portfolio for acute mania has significantly increased over the last years, and new agents are currently in the pipeline Additionally, new targets for drug development will emerge; Proteinkinase C inhibition is one example of a mechanism with some recent evidence of efficacy However, given the substantial number of medications available, it will become more essential that new medications show additional benefits besides being effective antimanic agents Most clinicians are likely to prefer antimanic drugs which also have established long term, prophylactic efficacy not only against manic relapse, but also against depressive episodes or even more challenging, substances that also have antidepressant activity With the expanding range of drugs with evidence of efficacy in mania, psychiatrists as well as patients may reasonably place safety, tolerability, and evidence of good persistence over time on equal footing with efficacy in selecting and continuing a regimen Similarly, tolerability and ease of adhering to the prescribed dosage can benefit from selection of drug formulations with extended release properties and/or once daily dosing In a highly competive field, future research and Downloaded By: [World Federation of Societies of Biological Psychiatry] At: 11:39 19 May 2009 108 H Grunze et al development will have to take that into account at an earlier stage than in the past; it will not be enough if you have ‘‘just another antimanic drug’’ to be clinically accepted In addition, regulators may query increasingly what the advantage of a new mediction is compared to those available and place more extreme demands on safety studies before licensing Novel mechanisms of action, coupled with an at least as favourable benefit/risl profile than current drugs, are two components that may become desirable, if not essential for regulatory approval in the future Due to the fact that patients enrolled in most randomised trials are highly selected, it also appears important to conduct large, prospective trials in unselected populations in a methodological more rigourous manner as previously done in schizophrenia This will not necessarily improve the evidence base, but increase the confidence that a given evidence based treatment is also effectice in real world settings Likewise, systematic data adressing the issue of dealing with patients not responding to first-step treatments is highly needed Conclusions This update of the original WFSBP guideline from 2003 has been compiled to aid clinician’s choice when treating patients with acute mania, as the scientific evidence for established agents has significantly increased over the last five years, and new medications have become available Recommendations given in this guideline are based, wherever possible, on randomized, controlled, double-blind trials However, such studies not always reflect clinical realities and have their shortcomings, e.g., the exclusion of comorbid, suicidal, or medically ill patients, which may in turn lead to disappointment with some medictation in clinical practice Accordingly, adherence to these guidelines can be far from ensuring a successful outcome in every case However, it may be a helpful framework for the educated psychiatrist, planning the individual treatment of a patient, taking all sources of information and all available treatment options into account Acknowledgements We would like to specially thank Mrs Berenike Oppermann, WFSBP office Vienna, for general and editorial assistance Financial disclosures of principal authors Heinz Grunze received grants/research support, consulting fees and honoraria within the last years from Astra Zeneca, Bial, BMS, Eli Lilly, GlaxoSmith Kline, Janssen-Cilag, Organon, Pfizer Inc, Sanofi-Aventis, Servier, UBC and UCB Belgium Eduard Vieta received grants/research support, consulting fees and honoraria within the last years from AstraZeneca, Bial, Bristol-Myers, Eli Lilly, Forest Research Institute, Glaxo-Smith-Kline, Janssen-Cilag, Jazz, Lundbeck, Merck-Sharp and Dohme, Novartis, Organon, Otsuka, Pfizer Inc, Sanofi-Aventis, Servier, and UBC Siegfried Kasper received grants/research support, consulting fees and honoraria within the last years from AstraZeneca, Bristol-Myers Squibb, CSC, Eli Lilly, GlaxoSmithKline, Janssen Pharmaceutica, Lundbeck, MSD, Novartis, Organon, Pierre Fabre, Pfizer, Schwabe, Sepracor, Servier, Wyeth Guy Goodwin received grants/research support, consulting fees and honoraria within the last years from AstraZeneca, Bristol-Myers Squibb, Eisai, Eli Lilly, Lundbeck, P1Vital, Sanofi-Aventis, Servier and Wyeth Charles Bowden received grants/research support, consulting fees and honoraria within the last years from Abbott Laboratories, Astra Zeneca, BristolMyers Squibb, Elan Pharmaceuticals, GlaxoSmithKline, Janssen, Lilly Research, National Institute of Mental Health, Parke Davis, Pfizer, R.W Johnson Pharmaceutical Institute, Sanofi Synthelabo, Smith Kline Beecham, Stanley Medical Research Foundation and UCB Pharma, Inc Rasmus W Licht received research grants, consulting fees and honoraria within the last three years from Astra-Zeneca, Bristol-Myers 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